The p53 response: Emerging levels of co-factor complexity

DNA damage triggers a checkpoint response that involves a myriad of cellular responses including cell cycle arrest, DNA repair, and apoptosis, and defects in the DNA damage response pathway lead to tumour development [1]. The tumour suppressor protein p53 is a key player in the checkpoint response to DNA damage, and the precise regulation of p53 is critical for both the checkpoint response and the suppression of tumourigenesis. This is highlighted by the fact that the p53 gene is one of the most commonly mutated genes in human cancer; approximately 50% of human cancers contain p53 mutations while the other half are thought to contain alterations in components of the p53 pathway [2]. p53 is a nuclear transcription factor that affects cellular functions which include transcription, DNA synthesis and repair, cell cycle arrest, senescence, and apoptosis [3]. The central region of p53 contains the DNA-binding domain (DBD), the amino (N)-terminal region harbours a transcriptional activation domain together with a polyproline-rich region, and the carboxyl (C)-terminal region contains a regulatory domain which includes a nuclear localisation signal (NLS) and an oligomerisation function [4]. Under normal conditions, p53 is held in a latent inactive state but undergoes a significant increase in protein stability upon exposure to DNA damage. DNA damage stabilises p53 in part via the DNA damage signalling pathway that involves the sensor kinases, including ATM and ATR, and effector kinases, like Chk1 and Chk2, which leads to the transcriptional regulation of a variety of genes involved in cell cycle control and apoptosis [1] and [4]. Since the activation of p53 causes cell cycle arrest and apoptosis, aberrant activation of p53 would have dire consequences for an organism. p53 is therefore tightly controlled, and its activity is regulated at a multiplicity of levels. Whilst post-translational modification plays an important role in p53 regulation [5], an increasing array of co-factors are now known to influence p53 activity. Here, we will discuss our current understanding of the emerging co-factor complexity involved in regulating the p53 response